chrX-70035527-T-C

Variant names:

• chrX-70035527-T-C
• rs397516654
• NM_001399.5:c.1094T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PS3 PM1 PM5 PP2 PP5_Very_Strong BS2

The NM_001399.5(EDA):​c.1094T>C​(p.Val365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000431 in 1,205,588 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060818: Functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010).; SCV000630019: Experimental studies have shown that this missense change affects EDA function (PMID:19623212).; SCV001805476: Published functional studies demonstrate a damaging effect with reduced receptor binding and signaling capability compared to wildtype (Mues et al., 2010);; SCV004239086: in vitro experimental studies demonstrate that the signaling capacity of protein constructs containing p.Val365Ala are impaired even though cellular production, export and receptor binding are readily detectable.; SCV004046192: Functional studies suggest that the c.1094T>C (p.Val365Ala) variant may affect cell signaling pathways (PMID:19623212).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V365M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000045 (0 hom. 13 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 4.35
• Publications: 2 publications found

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060818: Functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010).; SCV000630019: Experimental studies have shown that this missense change affects EDA function (PMID: 19623212).; SCV001805476: Published functional studies demonstrate a damaging effect with reduced receptor binding and signaling capability compared to wildtype (Mues et al., 2010);; SCV004239086: in vitro experimental studies demonstrate that the signaling capacity of protein constructs containing p.Val365Ala are impaired even though cellular production, export and receptor binding are readily detectable.; SCV004046192: Functional studies suggest that the c.1094T>C (p.Val365Ala) variant may affect cell signaling pathways (PMID: 19623212).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_001399.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70035526-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1482275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked hypohidrotic ectodermal dysplasia, tooth agenesis, selective, X-linked, 1, tooth agenesis.
• PP5: Variant X-70035527-T-C is Pathogenic according to our data. Variant chrX-70035527-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 49 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	NM_001399.5	MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 8 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.1088T>C	p.Val363Ala	missense	Exon 8 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.1085T>C	p.Val362Ala	missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 8 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.1088T>C	p.Val363Ala	missense	Exon 8 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.1079T>C	p.Val360Ala	missense	Exon 8 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes AF: 0.0000279 AC: 3 AN: 107573 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000575

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182595 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000446 AC: 49 AN: 1098015 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 363371

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000558 AC: 47 AN: 841954

Other (OTH) AF: 0.0000217 AC: 1 AN: 46094

GnomAD4 genome AF: 0.0000279 AC: 3 AN: 107573 Hom.: 0 Cov.: 21 AF XY: 0.0000334 AC XY: 1 AN XY: 29983

African (AFR) AF: 0.00 AC: 0 AN: 29419

American (AMR) AF: 0.00 AC: 0 AN: 9807

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2581

East Asian (EAS) AF: 0.00 AC: 0 AN: 3420

South Asian (SAS) AF: 0.00 AC: 0 AN: 2349

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000575 AC: 3 AN: 52170

Other (OTH) AF: 0.00 AC: 0 AN: 1422

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	EDA-related disorder (1)
1	-	-	Hypodontia (1)
1	-	-	Hypohidrotic X-linked ectodermal dysplasia (2)
1	-	-	Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	Tooth agenesis, selective, X-linked, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.35	N
PhyloP100		4.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.52	N
REVEL	Pathogenic	0.67
Sift	Benign	0.047	D
Sift4G	Benign	0.087	T
Polyphen		0.39	B
Vest4		0.16
MVP		1.0
MPC		1.1
ClinPred		0.46	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.89
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516654; hg19: chrX-69255377;